Abstract 3595: Mesenchymal stem cells play crucial roles in the generation of osteogenic prostate to bone metastases

Abstract

Abstract The skeleton is a common target for prostate metastases. In bone, prostate cancer cells induce extensive bone formation/osteogenesis by promoting osteoblast differentiation. This results in painful bony lesions that are incurable. The precise mechanisms through which prostate cancer cells induce bone formation are not well understood. Analysis of human and mouse specimens of prostate to bone metastasis demonstrate the presence of MSCs (smooth muscle actin positive). Given that MSCs are precursors of osteoblasts, we hypothesizes that MSC recruitment to the bone microenvironment would contribute to the formation of osteoblastic lesions and enhance tumor progression. Methodology: Using in-vitro and in-vivo studies we aim to elucidate the effects of MSC's on prostate tumor progression in bone. To determine the effect of the MSCs on the growth of the prostate cancer cells, mouse MSCs were directly co-cultured at various ratios with luciferase expressing PAIII prostate cancer cells for 24-96 hours. In-vivo, mice were intratibially inoculated with either PAIIIs, PAIIIs/MSCs (1:1), or MSCs (n=8/group, 104 total cells in 20µl). Tumor growth was measured over 15 days using luminescence imaging. Subsequently the tibias were collected for x-ray, micro CT, and histological analysis. Results: In-vitro MSCs inhibited the growth of the PAIII cells from 24 to 96 hours. At a 1:1 ratio, MSCs inhibited PAIII growth by up to 55% at 96 hours (p<0.05). A cleaved caspase 3 western blot of the lysates of PAIIIs treated with MSC CM provides evidence that soluble factors from the MSCs are inducing caspase dependent apoptosis. Consistent with our in vitro observations, we observed in vivo that at day 11, the average tumor size in the PaIII/MSC (1:1 ratio) group was 57.7% significantly smaller than the PAIII group alone (p<0.05). However by day 15 the tumors were growing at comparable rates. Tumor bearing tibias were X-rayed and an overall decrease in tumor-induced osteolysis was observed between the PAIII/MSC and PAIII groups. μCT scans of tumor bearing bones show an increase in bone volume in bones injected with MSCs alone and PaIII/MSCs when compared to PAIIIs, a finding that was consistent with X-ray and hisotmorphometrical data. Conclusions: In conclusion we have found that in-vitro and in-vivo MSCs have an early inhibitory effect on the growth of prostate tumor cells. This impact on growth is coupled to an apparent decrease in tumor-induced osteolysis and increase in osteogenesis. Currently, we are examining 1) the impact of the MSCs on tumor-induced osteogenesis and 2) identifying the MSC derived factors that are inhibiting prostate cancer growth. Understanding the role of MSCs in the prostate tumor-bone microenvironment will lead to the identification of new therapeutic targets to treat the disease. Citation Format: Jeremy Jonathan Mcguire, Gemma Shay, Leah Cook, Jeremy Frieling, Conor Lynch. Mesenchymal stem cells play crucial roles in the generation of osteogenic prostate to bone metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3595. doi:10.1158/1538-7445.AM2014-3595